A GWAS meta-analysis of alpha angle suggests cam-type morphology may be a specific feature of hip osteoarthritis in older adults

Benjamin G Faber* (Corresponding Author), April E. Hartley, Raja Ebsim, Cindy G. Boer, Fiona Saunders, Jenny Gregory, Richard Malcolm Aspden, Nicholas C Harvey, Lorraine Southam, William Giles, Christine L. Le Maitre, J. Mark Wilkinson, Joyce B.J. van Meurs, Eleftheria Zeggini, Timothy Cootes, Claudia Lindner, John P. Kemp, George Davey Smith, Jonathan H. Tobias

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives
To examine the genetic architecture of cam morphology, using alpha angle (AA) as a proxy measure, we conducted an AA genome wide association study (GWAS), followed by Mendelian randomisation (MR) to evaluate its causal relationship with hip osteoarthritis (HOA).
Methods
Observational analyses examined associations between AA derived from hip DXA scans in UK Biobank (UKB), and radiographic HOA (rHOA) and subsequent total hip replacement (THR). Afterwards, an AA GWAS meta-analysis was performed (n=44,214), using AA previously derived in the Rotterdam Study (RS). Linkage disequilibrium score regression assessed the genetic correlation between AA and HOA. Genetic associations with PResults
DXA-derived AA showed expected associations between AA and rHOA (OR 1.63 [95% CI 1.58-1.67]) and THR (HR 1.45 [1.33-1.59]) in UKB. The heritability of AA was 10% and AA had a moderate genetic correlation with HOA (rg=0.26 [0.10-0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on HOA risk (inverse variance weighted (IVW): OR=1.84 [1.14-2.96], P 0.01). In contrast, genetic predisposition for HOA had stronger evidence of a causal effect on increased
AA (IVW: β=0.09 [0.04-0.13], P 4.58 x 10-05).
Conclusions
Expected observational associations between AA and related clinical outcomes provided facevalidity for the DXA-derived AA measures. Evidence of bidirectional associations between AA and HOA, particularly in the reverse direction, suggests that hip shape modelling secondary to a genetic predisposition to HOA contributes to the well-established relationship between HOA and cam morphology in older adults.
Original languageEnglish
JournalArthritis & Rheumatology
Early online date20 Jan 2023
DOIs
Publication statusE-pub ahead of print - 20 Jan 2023

Keywords

  • Genome Wide Association Studies,
  • osteoarthritis
  • femoro-acetabular impingement
  • imaging
  • alpha angle

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